Salmon calcitonin is a peptide hormone that decreases uptake of calcium from bone. When used to treat bone-related diseases and calcium disorders (such as osteoporosis, Paget's disease, hypercalcemia of malignancy, and the like), it has the effect of helping maintain bone density. Many types of calcitonin have been isolated, such as human calcitonin, salmon calcitonin, eel calcitonin, elkatonin, porcine calcitonin, and chicken calcitonin. There is significant structural non-homology among the various calcitonin types. For example, there is 50% identity between the amino acids making up human calcitonin and those making up salmon calcitonin.
Salmon calcitonin used in the prior art has usually been administered by injection or by nasal administration. However, these modes of administering the calcitonin are significantly less convenient than oral administration and involve more patient discomfort. Often this inconvenience or discomfort results in substantial patient noncompliance with a treatment regimen. However, the prior art is not believed to have reported an ability to achieve reproducible blood levels of peptides such as salmon calcitonin when administered orally. This is believed to be because these peptides lack sufficient stability in the gastrointestinal tract, and tend to be poorly transported through intestinal walls into the blood.
Proteolytic enzymes of both the stomach and intestines may degrade salmon calcitonin, rendering it inactive before the calcitonin can be absorbed into the bloodstream. Any salmon calcitonin that survives proteolytic degradation by proteases of the stomach (typically having acidic pH optima) is later confronted with proteases of the small intestine and enzymes secreted by the pancreas (typically having neutral to basic pH optima). Other difficulties arising from the oral administration of salmon calcitonin involve the relatively large size of the molecule, and the charge distribution it carries. This may make it more difficult for salmon calcitonin to penetrate the mucus along intestinal walls or to cross the intestinal brush border membrane into the blood. These additional problems may further contribute to the limited bioavailability of salmon calcitonin.
U.S. Pat. No. 5,912,014 (the '014 patent) to Stern et al. describes a therapeutically effective oral pharmaceutical composition for delivering salmon calcitonin into the small intestine. According to that patent, it is believed that protecting the salmon calcitonin with an enteric coating can reduce the likelihood of proteolytic degradation of the salmon calcitonin in the stomach. Although the patent describes salmon calcitonin administration in a tablet form, the patent does not disclose a commercially viable dosage form comprising a peptide generally, nor does it describe a method of making such a dosage form. For example, during the compression phase of a composition prepared according to the '014 patent, it was found that some material would irreversibly stick to the tooling surface. Moreover, a monolayer tablet prototype exhibited poor stability when stored at ambient conditions. The '014 patent also does not describe solutions to the problems that arise in combining peptides, surfactants, and pH-lowering agents in a single enteric coated dosage form for production at a commercial scale.
Notwithstanding the foregoing, there is a need in the art for a commercially viable dosage form that maintains peptide stability in the presence of pH-lowering agents.